Emesis is a serious adverse reaction very frequently observed in patients administered with a cancer chemotherapeutic agent and patients receiving radiation therapy, and therefore, it is highly important to control emesis as an auxiliary therapy for sufficient cancer treatment. It was reported that emesis due to cancer treatment was effectively suppressed by intravenously administration of a large amount of 4-amino-5-chloro-N-[(2-diethylamino)ethyl]-2-methoxybenzamide (Non-patent document 2), which is an amide derivative developed in the middle of 1960s as an antiemetic drug or a digestive function promoting agent (nonproprietary name “metoclopramide”, see, for example, Non-patent document 1), and it became possible to control emesis to a certain extent in cancer treatments. Since then, a wide variety of substituted benzoic acid amide derivatives and heterocyclic carboxylic acid amide derivatives have been synthesized and their pharmacological properties were studied [for example, Non-patent document 3 and Patent documents 1 and 2]. However, although metoclopramide suppresses mild emesis via an antagonistic action on the dopamine D2 receptor, it fails to suppress emesis caused by anticancer agents such as cisplatin at usual doses. Further, since compounds having the benzamide structure have a dopamine blocking action and a central nerve system depressing action, they cause undesirable side reactions (for example, sedation, ataxic response, diarrhea and akathisia).
The suppressing effect against cisplatin-induced emesis obtained by the administration of a large amount of metoclopramide is considered to be attributable to a serotonin 5-HT3 receptor antagonistic action [Non-patent document 4], and various serotonin 5-HT3 antagonists have been developed. These compounds having serotonin 5-HT3 receptor antagonistic action have been revealed to be effective for suppression of nausea and emesis as adverse reactions caused by anticancer agents such as cisplatin and radiotherapy, and several medicaments have been clinically used. Examples of the clinically used serotonin 5-HT3 receptor antagonists include antiemetic drugs such as ondansetron, granisetron, which is a lactam derivative, and tropisetron, which is an indole derivative [Non-patent document 5, Patent documents 3 and 4].
In the late 1970s, a benzoate derivative, MDL-72222 [Patent document 5 and Non-patent document 6], and an amide derivative, ICS 205-930 [Patent document 6 and Non-patent document 6] were discovered, which have a serotonin 5-HT3 receptor-selective antagonistic action. Since then, several benzoic acid amide derivatives and heterocyclic carboxylic acid derivatives as serotonin 5-HT3 receptor antagonists have been proposed [for example, Patent documents 7 and 8]. It has been reported that these compounds are effective for not only nausea or emesis induced by anticancer agents, migraine, arrhythmia and the like, but also schizophrenia, anxiety neurosis, dependence on alcohol, nicotine, narcotics, and the like [Patent document 9 and Non-patent document 7].
The serotonin 5-HT3 receptor abundantly exists in the vagus nerve afferent neurons in the intestinal tract, and is involved in regulations of sensation and reflex reaction in response to stimuli in the intestinal tract to greatly affect the gastrointestinal motility. Several serotonin 5-HT3 receptor antagonists as lactam derivatives are considered to be useful for the treatment of gastrointestinal disorders associated with upper intestinal motility [Patent document 10], and serotonin 5-HT3 receptor antagonists as benzamide derivatives [Patent document 11] are considered to be useful for the treatment of gastrointestinal motility disorders. Further, serotonin 5-HT3 receptor antagonists as amide derivatives having the azabicyclic system [Patent documents 10 and 12] are considered to be useful for the treatment of irritable bowel syndrome (IBS). However, these serotonin 5-HT3 receptor antagonists suffer from a problem that they cause constipation symptoms as adverse reactions. For example, it was found that “alosetron” [Patent document 13], which is a therapeutic agent for IBS as a lactam derivative, caused serious ischemic colitis and constipation as adverse reactions, and was withdrawn from the market in November 2000. Then, this medicament was reapproved under a strictly restricted use limited to female patients with diarrhea-dominant IBS.
It has been found that benzoxazole derivatives, of which development as digestive function regulating drugs is being studied, have serotonin 5-HT3 receptor antagonistic action [Patent document 14]. Further, amide derivatives having a benzoic acid skeleton disubstituted with an alkylenedioxy group in the 2nd and 3rd positions have been disclosed as serotonin 5-HT3 receptor antagonists [Patent document 15]. As described above, several antiemetic drugs and digestive function regulating drugs having the serotonin 5-HT3 receptor antagonistic action have been reported. However, none of these compounds have a urea functional group.
N-(4-Amino-5-chloro-2-methoxyphenyl)-4-benzylpiperazine-1-carboxyamide, a urea derivative of aniline, is disclosed in Patent document 16. Although this publication discloses that the aforementioned substance has a tranquilizing activity, it neither suggests nor teaches that the aforementioned substance exhibits an action selective to the serotonin 5-HT3 receptor, or that the aforementioned substance has an antiemetic action or an action on the gastrointestinal tract.
Further, N-(4,5-dichlorophenyl)-4-methylpiperazine-1-carboxyamide, a urea derivative, is known to have an antihypertensive action [Non-patent document 8], and N-(3,5-trifluoromethylphenyl)-4-methylpiperazine-1-carboxyamide is known to have an anticonvulsant action [Non-patent document 9]. However, these publications do not suggest nor teach that the aforementioned urea derivatives have an action selective to the serotonin 5-HT3 receptor, and also do not disclose that these compounds have an antiemetic action or an action on the gastrointestinal tract.    Non-patent document 1: Merck Index, 10th edition, 6019 (1983)    Non-patent document 2: N. Engl. J. Med., 305, 905 (1981)    Non-patent document 3: Ann. Rep. Med. Chem., 38, 89 (2003)    Patent document 1: U.S. Pat. No. 4,207,327, p. 2    Patent document 2: Japanese Patent Unexamined Publication (Kokai) No. 60-123485, p. 4    Non-patent document 4: Br. J. Pharmacol, 88, 497 (1986)    Non-patent document 5: Drugs of the Future, 14 (9), 875 (1989)    Patent document 3: European Patent No. 201165, p. 3    Patent document 4: European Patent No. 226226, p. 2    Patent document 5: Japanese Patent Unexamined Publication No. 58-978, p. 2    Non-patent document 6: Trends in Pharmaceutical Sciences, 8, 44 (1987)    Patent document 6: Japanese Patent Unexamined Publication No. 59-36675, p. 17    Patent document 7: Japanese Patent Unexamined Publication No. 61-275276, p. 11    Patent document 8: Japanese Patent Unexamined Publication No. 62-252764, p. 10    Patent document 9: Japanese Patent Unexamined Publication No. 1-31729, p. 4 and    Non-patent document 7: Eur. J. Pharmcol., 151, 159 (1988)    Patent document 10: European Patent No. 189002, p. 4    Patent document 11: European Patent No. 36269, p. 2    Patent document 12: European Patent No. 377967, p. 8    Patent document 13: Japanese Patent Unexamined Publication No. 1-151578, p. 6    Patent document 14: Japanese Patent Unexamined Publication No. 6-345744, p. 2    Patent document 15: International Patent Publication WO92/10494, p. 10    Patent document 16: Belgian Patent No. 866057, p. 3    Non-patent document 8: J. Med. Chem., 12, 551 (1969)    Non-patent document 9: Indian J. Chem., Sect B., 24B(9), 934 (1985)